PATHOLOGY OF VASCULAR SKIN LESIONS - PART 8 doc

Another characteristic feature of patch stage lesions of Kaposi’s sarcoma is the presence of scattered necrotic endothelial cells, a feature that has been emphasized at both the conventi

Fig 7 AIDS-associated Kaposi’s sarcoma involving the oral mucosa.

adnexae and blood vessels, producing the so-called promontory sign (71) (Fig 9) In

other areas, the blood vessels infiltrate between collagen bundles of the dermis, giving the appearance that they are “dissecting” the stroma In rare instances, the newly formed

blood vessels form clusters that resemble small hemangiomas (71,74) The inflammatory

cells present are predominantly lymphocytes and plasma cells The presence of plasma cells around newly formed irregular blood vessels is a helpful clue in the histopathologic

diagnosis of the patch stage of Kaposi’s sarcoma (71) Another characteristic feature of

patch stage lesions of Kaposi’s sarcoma is the presence of scattered necrotic endothelial

cells, a feature that has been emphasized at both the conventional microscopy (77) and ultrastructural level (41) Hemosiderin-laden macrophages are another feature frequently

found in early lesions of Kaposi’s sarcoma The histopathologic features just described for the patch lesions can also be seen in clinically normal areas of skin in patients who have Kaposi’s sarcoma elsewhere, which supports the notion of the diffuseness of the

process from its inception (79,80).

Plaque lesions of Kaposi’s sarcoma tend to involve the entire dermis and even the upper part of the subcutaneous fat At this stage, there is an increased number of spindle cells arranged in short fascicles between collagen bundles centered around proliferating vascular channels The spindle cells line irregularly shaped, slit-like vascular spaces that contain isolated erythrocytes They display minimal or no atypia, with only a few to no mitotic figures.

Fig 8 Histopathologic features of patch stage Kaposi’s sarcoma (A) At scanning magnification, the lesions consists of increased numbers of jagged spaces at different levels of the dermis (B) Higher magnification shows that the jagged spaces are lined by thin endothelial cells (C) At this

point it is possible to see inflammatory infiltrate with some plasma cells and extravasated rocytes

eryth-When the number of spindle cells increases, lesions of Kaposi’s sarcoma become nodular Then the spindle cells are arranged in interwoven fascicles with erythrocytes scattered in the interstices (Fig 10) Nuclear atypia, pleomorphism, and mitotic figures may be seen but are usually not very prominent In rare instances, however, especially

Fig 9 Histopathologic features in plaque lesions of Kaposi’s sarcoma (A) Scanning power shows involvement of the upper part of the dermis by the neoplastic process (B) Higher magnification shows irregular vascular spaces and inflammatory infiltrate (C) The “promontory” sign is evident around preexisting capillaries (D) Numerous plasma cells are present in the stroma surrounding

the areas of “promontory” sign

Fig 10 Histopathologic features in nodular lesions of Kaposi’s sarcoma (A) Scanning cation shows a well-circumscribed cellular nodule in the dermis (B) Higher magnification dem-

magnifi-onstrates that the nodule is composed of fascicles of spindle cells Some congestive vascular

lumina are also seen (C) Spindle cells are monomorphous, and nuclear atypia, pleomorphism, and

mitotic figures are not usually prominent

in the African variant (81), a significant number of mitotic figures and atypical cells may

be seen in lesions of Kaposi’s sarcoma A rather characteristic, but probably not specific, finding is the presence of the so-called hyaline globules Although these are most common in the plaque and nodular lesions of Kaposi’s sarcoma, they can be present at any stage of the disease These globules are periodic acid-Schiff (PAS)-positive and diastase-resistant, consist of eosinophilic spherules measuring between 1 and 10 µm, and are located both intra- and extracellularly Most likely these hyaline globules represent degenerated erythrocytes that are phagocytized and confined to the phagolysosomes of

the neoplastic cells (82–85) These globules have been also described in other

vas-cular proliferations such as angiosarcomas, pyogenic granulomas, and granulation

tissue (84).

In rare instances, lesions of Kaposi’s sarcoma may present clinically as bullous lesions with histopathologic features of a lymphangioma These lesions show irregular vascular channels lined by a single layer of flattened endothelial cells devoid of erythrocytes

within the dermis (86–94) The absence of hemosiderin deposits and the scarcity of

spindle cells also contribute to a lymphangiomatous appearance of the lesions ally, the lymphangiomatous pattern can be seen focally within an otherwise stereotypical lesion of Kaposi’s sarcoma There have been patients with classic Kaposi’s sarcoma in which some lesions showed a lymphangioma-like pattern, whereas other lesions of the same patient exhibited the typical findings associated with Kaposi’s sarcoma, with abun-

Occasion-dant extravasated erythrocytes and hemosiderin deposits Chronic lymphedema (86) and/

or the use of electron beam therapy (94) on the involved extremity may be responsible

for the formation of the lymphangioma-like lesions in Kaposi’s sarcoma.

From a histogenetic point of view, current evidence suggests that Kaposi’s sarcoma is

a proliferative process Ultrastructural and immunohistochemical studies have shown that

the spindle cell component shows endothelial differentiation (95,96) Whether this sents endothelium of blood vessels or lymphatics remains to be determined (97–107) Well-

repre-formed vessels in lesions of Kaposi’s sarcoma are lined by cells that are positive for factor VIII-related antigen, but studies for this marker in neoplastic spindle cells have provided

conflicting results (96,99,102–109) In contrast, Ulex europaeus I lectin has consistently been detected in the spindle cells (99,108) Rutgers et al (97) concluded that spindle cells

in Kaposi’s sarcoma are blood vascular endothelial cells, because they stain with clonal antibodies OKM5, anti-E92, and HCl, which react with blood capillary endothelium, but not with lymphatic endothelium Identical conclusions were reported by Scully et al.

mono-(109) on the basis of the immunoreactivity of spindle cells with the antibody B721.

Russell Jones et al (99,108) noted that immunoreactivity of the spindle cells varies

with the stage and type of the lesions Early patch stage lesions have the profile of a lymphatic lesion because the cells are positive for the antibody EN-4, which stain all types of endothelial cells, but are negative with the antibody PAL-E, which is specific for blood vessel endothelium Nodular lesions of Kaposi’s sarcoma stain with EN-4 and

express variable immunoreactivity with PAL-E (99,108) Beckstead et al (101) also

favored lymphatic endothelial differentiation because of the lack of HLA-DR/Ia and alkaline phosphatase and the intense staining with 5' nucleotidase In contrast, the presence of abundant laminin and type IV collagen surrounding many of the individual spindle cells has been interpreted as evidence favoring a blood vascular endothelium

rather than lymphatic endothelium differentiation (110–112) More recently, Weich et al.

(113) have suggested a close relationship between the Kaposi’s sarcoma cell and the

vascular smooth muscle cell, since the tumors express mRNA for α-smooth muscle actin Different investigators have found that the Kaposi’s sarcoma cells express the CD34 antigen, also known as the human progenitor cell antigen This is a 105–120-kDa single- chain transmembrane glycoprotein expressed constitutively by endothelial cells of small

blood, but not lymphatic, vessels in several tissues (114–118).

A nonvascular origin for the spindle cells of the Kaposi’s sarcoma has also been suggested, based on the presence of many factor XIIIa-positive spindle cells in the lesions, suggesting that the factor XIIIa-expressing dermal dendrocyte (a member of the mono- nuclear phagocytic system) may be the cell of origin for the spindle-shaped cells of

Kaposi’s sarcoma (119,120) Other authors, however, believe that these factor

XIIIa-positive dendritic cells represent reactive hyperplasia of dermal dendrocytes, rather than

neoplastic cells (107) More recently, vascular endothelial growth factor receptor-3 (VEGFR-3) (121–124) and podoplanin (123,125), two relatively sensitive and specific

markers for lymphatic endothelium, have been identified in most Kaposi’s sarcomas, supporting a lymphatic differentiation for this neoplasm.

Ultrastructural studies have documented that under electron microscopy most of the spindle cells exhibit characteristics of endothelial cells, although a few of them also show

features of pericytes and fibroblasts (126) The cells surrounding vascular spaces show

few intercellular junctions, with gaps between them A fragmented basal lamina encircles the luminal cells in absence of pericytes These ultrastructural features seem to be more compatible with lymphatic than blood vascular differentiation, but it is possible that their

absence may be the result of the dilation of blood vessels (41).

The differential diagnosis of Kaposi’s sarcoma from pseudo-Kaposi’s sarcoma lesions

is usually straightforward In both the acroangiodermatitis and arteriovenous tion variants of pseudo-Kaposi’s sarcoma lesions, the blood vessels of the papillary dermis are involved, demonstrating a lobular proliferation of round, dilated, thick-walled

malforma-capillaries, with plump endothelial cells (127) This vascular proliferation is

superim-posed on a background of dermal fibrosis, erythrocyte extravasation, and abundant hemosiderin The irregular jagged vascular channels with slit-like lumina surrounding preexisting capillaries, found in early lesions of Kaposi’s sarcoma, are not seen Benign lymphangioendothelioma can be also mistaken for early lymphangioma-like lesions of Kaposi’s sarcoma Similarities include thin-walled, endothelium-lined vascu- lar spaces between collagen bundles that appear to “dissect” the dermis However, these vascular spaces of benign lymphangioendothelioma are usually arranged horizontally in the dermis and show no tendency to surround preexisting blood vessels as in Kaposi’s sarcoma Furthermore, the absence of extravasated erythrocytes, hemosiderin, and plasma cells is also helpful The clinical appearance of the lesion is helpful, too, because benign lymphangioendothelioma presents as a solitary lesion.

Hobnail hemangioma also shares common histopathologic features with Kaposi’s sarcoma, especially at the periphery of the lesion In these areas, there are irregular angulated vascular lumina that appear to be dissecting collagen bundles and abundant hemosiderin, raising the possibility of early lesions of Kaposi’s sarcoma However, in the central areas of hobnail hemangioma, there are widely dilated vascular lumina with intraluminal papillary projections, prominent endothelial cells, and frequent fibrin thrombi These features are not seen in Kaposi’s sarcoma.

Spindle cell hemangioma is frequently confused with nodules of Kaposi’s sarcoma because in both entities there are fascicles of spindle cells with slit-like vascular spaces containing erythrocytes However, spindle cell hemangioma shows dilated blood vessels and areas of epithelioid cells, with prominent cytoplasmic vacuoles, which are not seen

in nodules of Kaposi’s sarcoma.

Kaposiform hemangioendothelioma bears a striking resemblance to the nodular lesions

of Kaposi’s sarcoma; however, the clinical settings are different Kaposi’s sarcoma is uncommon in infancy, and kaposiform hemangioendothelioma is a solitary neoplasm Furthermore, histopathologically, kaposiform hemangioendothelioma shows a lobulated growth pattern and hemangioma-like areas, especially at the periphery of the lobules The biologic behavior of Kaposi’s sarcoma depends on the epidemiologic type of the disease and the immune status of the host There have been diverse opinions as to whether Kaposi’s sarcoma represents a reactive vascular proliferation or a true neoplastic prolif- eration Currently, there is a consensus that Kaposi’s sarcoma does not produce metasta- sis in the manner of conventional sarcomas, but rather it develops in a multifocal fashion

(128) This notion is based on the finding of changes in internal organs such as the lymph

nodes, gastrointestinal tract, lung, and kidney similar to those seen in the lesions of the patch stage of Kaposi’s sarcoma in the skin Despite the lack of metastatic potential, patients can succumb to the effects of Kaposi’s sarcoma Immunocompetent individuals affected with the classic variant of Kaposi’s sarcoma have a mortality rate between 10 and 20% after 10 years, whereas Kaposi’s sarcoma in AIDS patients has a far more aggressive course; the overall mortality rate is 41% and death occurs within a relatively short period

of time (129).

TREATMENT

The treatment of Kaposi’s sarcoma includes local and/or systemic therapy The priate selection of therapy in each case depends on the epidemiologic variant of the disease, the number of lesions, and the immune status of the patient In patients with AIDS, new antiretroviral therapies, in particular the protease inhibitors, appear to be changing the clinical course of Kaposi’s sarcoma Local therapies include liquid nitrogen cryotherapy, radiation therapy, laser therapy, and intradermal therapy with cytotoxic chemotherapy drugs or interferon Systemic therapies include limited intervention with interferon, with or without zidovudine, and more aggressive intervention with single or multiagent chemotherapy modalities Therapeutic options for the different clinical set-

appro-tings of Kaposi’s sarcoma have been recently reviewed by Tappero et al (10) The most recent alternatives consist of topical treatment with alitretinoin gel (130), and the admin- istration of liposomal doxorubicin (131) or vinorelbine (132).

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hemangioendothelioma (2,3) To avoid confusion, more logical denominations should be used for some of the vascular proliferations, currently covered by this term (3) (Table 2).

CLINICAL FEATURES

Epithelioid hemangioendothelioma is a low-grade angiosarcoma first described by

Weiss and Enzinger in 1982 (4) It usually appears as a solitary, slightly painful soft tissue tumor (5), although similar lesions have also been reported in the skin (6–13) and oral cavity (14–16) In some cases the lesions consist of ulcerated nodules (17) Epithelioid hemangioendotheliomas may occur at any age, but they are rare during childhood (18).

They affect both sexes in approximately equal proportion At least one-half of the cases

are closely associated with or arise within a vessel, usually a vein (5) In some of these

cases, the occlusion of the vessel accounts for most of the symptoms, such as edema and/

or thrombophlebitis Occasional associations with other neoplasms have been reported including epithelioid dermatofibroma and a Spitz nevus, suggesting an underlying “epi- thelioid” predisposition that could be responsible for the epithelioid appearance in all

three tumors (19) Multiple eruptive lesions involving the right arm and humerus have also been described (20) (Fig 11) A case of an epithelioid hemangioendothelioma in association with a spindle cell hemangioendothelioma has also been published (21).

Before a diagnosis of primary cutaneous epithelioid hemangioendothelioma is lished, the possibility of cutaneous metastasis from a visceral epithelioid hemangioen-

estab-dothelioma should be excluded (22,23).

Table 2 Proposed Terminology for Neoplasms Currently Named Hemangioendothelioma

Conventional terminology Proposed terminology

Benign vascular proliferations

Malignant vascular proliferations

epithelioid angiosarcoma Endovascular papillary hemangioendothelioma Well-differentiated endovascular

papillary angiosarcoma

of children (Dabska’s tumor)

composite angiosarcoma

HISTOPATHOLOGIC FEATURES

Cutaneous epithelioid hemangioendothelioma presents as a circumscribed dermal nodule with an overlying acanthotic epidermis (Fig 12) In some cases there is a striking

acrosyringeal proliferation, which resembles an eccrine syringofibroadenoma (13) The

neoplasm is composed of cords, strands, and nests of plump, epithelioid cells embedded

in a fibromyxoid or sclerotic stroma Many of the neoplastic cells contain vacuoles in their cytoplasm as a sign of primitive vascular differentiation Slight cellular pleomor- phism and occasional mitotic figures may be seen Rarely, large, distinct vascular chan- nels are present mainly in the central areas of the neoplasm Occasionally, the stroma may

show foci of osseous metaplasia (24) Lesions that develop within a vessel extend

centrifugally from the lumen of the vascular structure to the adjacent soft tissue, preserving the architecture of the involved vessel The lumen is filled with necrotic debris and dense collagen.

In many cases epithelioid hemangioendotheliomas are difficult to differentiate from metastatic adenocarcinomas The latter usually contain vacuoles within the neoplastic

cells, while in the former there may be erythrocytes within the vacuoles (4,5,13,25).

Immunohistochemistry is also useful in this differential diagnosis The neoplastic cells

of epithelioid hemangioendothelioma express immunoreactivity for factor VIII-related

antigen, Ulex europaeus I lectin, CD31, and CD34 (1,5–10,13,25), but they may also stain with cytokeratins (25,26) and α-smooth muscle actin (13,25) The epithelioid forms of an-

giosarcoma involving the skin and superficial soft tissues can also mimic epithelioid gioendothelioma However, epithelioid angiosarcoma is composed of solid sheets of neoplastic cells, many of them atypical, with abundant mitotic figures and with necrosis

heman-occurring in both individual cells and large areas of the neoplasm (necrosis en masse)

Elec-tron microscopic studies in epithelioid hemangioendothelioma have demonstrated that the neoplastic cells show characteristics of endothelial cells, with well-developed basal lamina,

Fig 11 Eruptive multiple epithelioid hemangioendothelioma involving the anterior chest of an

adult man

Fig 12 Histopathologic features of epithelioid hemangioendothelioma (A) Low power shows a relative well-circumscribed nodule in the dermis (B) The cellular nodule is mostly solid, but vascular channels are also present (C) Cytoplasmic vacuolization is prominent in many neoplastic cells (D) Higher magnification demonstrates that neoplastic cells show an epithelioid appearance,

and many of them contain vacuoles in their cytoplasm Numerous erythrocytes are seen both inthe vacuoles and extravasated

pinocytotic vesicles, and occasional Weibel-Palade bodies They differ from normal

endot-helial cells by the presence of abundant intermediate filaments that fill the cytoplasm (27).

TREATMENT

Treatment of superficial forms of epithelioid hemangioendothelioma includes wide excision and clinical evaluation of the regional lymph nodes, since this is the most common metastatic site Metastases occur more frequently in the histopathologically malignant forms Fewer than half the patients who developed metastases died of their disease, because most of the metastases occur in regional lymph nodes and excision of

these structures is curative, or provides at least long-term disease-free survival (1).

However, the follow-up of a recent series of 30 patients with epithelioid helioma of skin and soft tissues demonstrated systemic metastases in 21% of the cases,

hemangioendot-and 17% of the patients died because of the tumor (25) Therefore, epithelioid

heman-gioendothelioma of the soft tissues should be regarded as a fully malignant, rather than borderline, vascular neoplasm, although the prognosis is better than in conventional angiosarcoma.

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